Resveratrol Inhibits Renal Fibrosis in the Obstructed Kidney Potential Role in Deacetylation of Smad3
Resveratrol Inhibits Renal Fibrosis in the Obstructed Kidney Potential Role in Deacetylation of Smad3
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DOI：
10.2353/ajpath.2010.090923
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发表时间：
2010-09-01
影响因子：
6
通讯作者：
Nikolic-Paterson, David J.
中科院分区：
文献类型：
--
作者：
Li, Jinhua;Qu, Xinli;Nikolic-Paterson, David J.
转化生长因子-β 1 (TGF-β 1) 通过 Smad3 信号通路促进组织纤维化。虽然已知磷酸化可调节 Smad3 功能，但最近的体外研究表明乙酰化也可能调节 Smad3 功能。本研究调查了肾纤维化中的 Smad3 乙酰化。 TGF-β1 刺激肾成纤维细胞和肾小管上皮细胞诱导 Smad3 乙酰化和磷酸化。白藜芦醇是烟酰胺腺嘌呤二核苷酸 (NAD) 依赖性蛋白脱乙酰酶 SIRT1 的激活剂，可逆转 Smad3 的乙酰化而不是磷酸化，并抑制 TGF-β1 诱导的 IV 型胶原和纤连蛋白 mRNA 水平的上调。 SIRT1 表达的敲低消除了白藜芦醇的抑制作用，免疫共沉淀研究提供了乙酰化 Smad3 和 SIRT1 之间相互作用的直接证据。然后在单向输尿管梗阻 (UUO) 模型中检查 Smad3 乙酰化在肾纤维化中的作用。免疫沉淀研究显示，UUO 第 2 天时 Smad3 发生乙酰化和磷酸化，并持续到第 7 天，与间质纤维化的发展相关。在UUO第2天，白藜芦醇抑制Smad3的乙酰化，但不抑制磷酸化，并且在UUO第7天，白藜芦醇治疗抑制间质纤维化。总之，这些研究支持 Smad3 乙酰化在肾纤维化中的病理作用，并表明 Smad3 去乙酰化可能是纤维化疾病的新治疗靶点。 （Am J Pathol 2010，177：1065-1071；DOI：10.2353/ajpath.2010.090923）
Transforming growth factor-beta 1 (TGF-beta 1) promotes tissue fibrosis through the Smad3 signaling pathway. While phosphorylation is known to regulate Smad3 function, recent in vitro studies have suggested that acetylation may also regulate Smad3 function. This study investigated Smad3 acetylation in renal fibrosis. TGF-beta 1 stimulation of renal fibroblasts and tubular epithelial cells induced Smad3 acetylation and phosphorylation. Resveratrol, an activator of the Nicotinamide adenine di nucleotide (NAD) dependent protein deacetylase SIRT1, reversed acetylation but not phosphorylation of Smad3 and inhibited TGF-beta 1-induced up-regulation of collagen IV and fibronectin mRNA levels. Knockdown of SIRT1 expression abolished the inhibitory effect of resveratrol, and co-immunoprecipitation studies provide direct evidence of an interaction between acetylated Smad3 and SIRT1. The role of Smad3 acetylation in renal fibrosis was then examined in the unilatend ureteric obstruction (UUO) model. Immunoprecipitation studies showed acetylation and phosphorylation of Smad3 by day 2 UUO, which was sustained to day 7 in association with development of interstitial fibrosis. Resveratrol inhibited acetylation but not phosphorylation of Smad3 at day 2 UUO, and resveratrol treatment inhibited interstitial fibrosis at day 7 UUO. In conclusion, these studies support a pathological role for Smad3 acetylation in renal fibrosis and suggest that deacetylation of Smad3 may be a novel therapeutic target for fibrotic disease. (Am J Pathol 2010, 177:1065-1071; DOI: 10.2353/ajpath.2010.090923)